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Robert H. Eckel, M.D. Professor of Medicine
Professor of Physiology and Biophysics Charles A. Boettcher II Chair in Atherosclerosis
University of Colorado Anschutz Medical Campus
“A Heavy Burden: Obesity and Diabetes"
Diabetes In and Out
University of Rochester School of Medicine and Dentistry March 12, 2016
Duality of Interests – Consultant/Advisory
Boards • ISIS Pharmaceuticals • Merck • Novo Nordisk • Regeneron/Sanofi
– Grants/Research Fellowships • ISIS Pharmaceuticals • UniQure
– Medical Education
• CMHC • Medscape • Medical Education
Resources • MedIntelligence • VOX Media
Objectives
• Discuss the etiologies of obesity and the science behind the defense of body weight (fat).
• Review the therapeutic options for treating obesity in patients with type 2 diabetes.
Genes Monogenic Polygenic
Environment Food availability Diet composition Physical activity Drugs
Pathway Adjustment Development Postnatal factors Epigenetic
Psychology Behavior patterns Depression Culture
Pathogenic Factors in Obesity
Rare Monogenic (<1%)
MODY (1-5%)
Common Gene Variants
15%
T2DM
5%
Obesity Additional variants with smaller effects? Less frequent variants with larger effects? Untranscribed DNA? Micro RNAs? Gene-gene interactions? Gene-environment interactions? Epigenetic effects?
Genetic Determinants of “T2DM” and Obesity
Only hypothesis generating
Prevention of Weight Gain • It’s all a matter of energy balance!
– In the absence of edematous disorders, if you’re burning less than you’re eating you gain weight
E Out < E In WT
Obesity Incidence Based on Energy Balance Calculations
• BMI – 25.0 kg/m2, Ht - 68”, Wt – 164 lb vs. • BMI – 30.0 kg/m2, Ht – 68”, Wt – 197 lb over 25 years is 10 kcal/day excess
Body Weight Regulation
SET OR SETTLING POINT?
Body Weight
Time
years months years
therapeutic space prevention
Schematic Representation of the Natural History of Obesity
Eckel RH, Kahn S et al: Diabetes Care 34:1424; JCEM 96:1654, 2011
Multiple Hormonal Signals Influence Food Intake
Adipose Tissue
Leptin Adiponectin
Gut
GLP-1 Ghrelin
PYY CCK
Pancreas
Amylin Insulin Hormonal
signals
Organ
Once obesity occurs, body fat is defended!
Long-Term Follow-Up of Behavioral Treatment for Obesity
Kramer, F.M. et al, Int J Obes 13:131, 1989
Preservation of Weight Loss by Different Interventions
Svetkey LP t al, JAMA 299:1139, 2008
The Biology of Reduced Obesity • ↓ leptin, ↑ghrelin, ↓ GLP-1
– ↑ appetite – ↑ preference for energy dense foods
• ↑ insulin sensitivity – ↓ adipose tissue TG lipolysis – ↓ pro-inflammatory cytokines – ↑ adipose tissue lipoprotein lipase – ↓ skeletal muscle lipoprotein lipase – ↑ CHO oxidation & ↑ fat storage
• ↓ physical activity Eckel RH, NEJM, 358:18, 2008
How much change in AT mass is needed to be
defended?
Let’s ask this question in walking-well normal weight women.
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
Control
Lipectomy
Chan
ge fr
om B
asel
ine
(%)
6 wk 12 mo
Total Body % Fat Changes: DXA
-2
-1.5
-1
-0.5
0
0.5
1 Control Lipectomy C
hang
es fr
om B
asel
ine
(%)
6 wk 12 mo
Hernandez TL et al, Obesity 19:1388, 2011
Change in Trunk Fat (DEXA) in Normal Weight Women after Suction Lipectomy
So even in walking-well normal weight women,
total body fat is defended one year after suction lipectomy - and perhaps in less favorable
locations!
Hernandez TL et al, Obesity 19:1388-95, 2011
The Complex Biology of Weight Regain after Weight Loss
MacLean PS et al, Obesity Rev Suppl 1: 45, 2015
Predictors of Weight Loss Maintenance: NWCR
• Energy Intake – avoid frying – substitute low-fat for high-fat
• Leisure Time Exercise – # of strenuous activities/wk – # of sweat episodes/wk
• Restraint Scale – Concern about dieting – Weight fluctuation
McGuire, M.T. et al, Obesity Res 7:334, 1999
Pharmacotherapy for Reduced-Obesity Maintenance
• Appetite typically increases after successful weight reduction, a predictor or weight regain.
• All pharmacological agents except orlistat used in obesity treatment work by reducing appetite and decreasing food intake.
• Anti-obesity drugs have been associated with improved weight-loss maintenance after 12 kg of weight reduction. – Johansson K et al, AJCN, 99:14, 2014
Weight Loss Maintenance in 20 Randomized Controlled Trials
Johansson K et al, AJCN, 99:14, 2014
Progression to Type 2 Diabetes
Ramlo-Halsted BA and Edelman SV. Prim Care 26:771, 1999; Nathan DM. NEJM 347:1342, 2002
Postprandial Glucose
0 5 -10 -5 10 15
∆ from normal
Diagnosis
Years From Diagnosis
Prandial defect occurs first.
At the time of diagnosis, ~50% of insulin secretory
capacity has been lossed.
Insulin Secretion Insulin Resistance
Fasting Glucose
Approaches to Weight Loss in Patients with
Type 2 Diabetes
Weight Effects of Glucose-Lowering Medications
Eckel RH et al. Diabetes Care 34:1424-1430; 2011
Medication class Weight effects GLP-1 analogs ↓ Metformin ± or ↓
Bromocryptine ↓
SGLT2 inhibitors ↓
α-Glucosidase inhibitors ±
DPP-4 inhibitors ± Insulin ↑ Sulfonylureas ↑ Glinides ↑
Thiazolidinediones ↑
Approaches to Weight Loss in Patients with Type 2 Diabetes
• Lifestyle • Behavioral modification • Medications • Metabolic surgery
Weight Loss in T2DM and Less CVD: Did Look AHEAD Answer All the Questions?
• Primary Objective – To assess the long-term (11.5 yr) effects of an intensive weight loss program over 4 years in overweight and obese subjects with type 2 diabetes. – n = 5145 men and women in 16 study centers – Weight loss vs. support and education – age: 45-74 yr – BMI > 25 kg/m2 – Primary outcome – time to a major CVD event – Secondary outcomes – many – Study stopped early for no benefit on primary outcome
Look AHEAD Study Group, NEJM 369:145, 2013
Look AHEAD: Weight Change
Look AHEAD Study Group, NEJM 369:145, 2013
Intervention
Control
Look AHEAD: Glycated Hb Change
Look AHEAD Study Group, NEJM 369:145, 2013
Intervention
Control
Look AHEAD: Change in BP
Look AHEAD Study Group, NEJM 369:145, 2013
Intervention
Control
Look AHEAD: Change in HDL-C
Look AHEAD Study Group, NEJM 369:145, 2013
Intervention
Control
Look AHEAD: Change in TG
Look AHEAD Study Group, NEJM 369:145, 2013
Intervention
Control
Look AHEAD: Change in LDL-C
Look AHEAD Study Group, NEJM 369:145, 2013
Intervention
Control
Look AHEAD: Change in Rx
Look AHEAD Study Group, NEJM 369:145, 2013
Intervention
Control
Look AHEAD: Primary MACE Outcome
Look AHEAD Study Group, NEJM 369:145, 2013
Intervention
Control
Why Did Look AHEAD Fail? • Insufficient power?
– In particular subgroups • No CVD history?
• More weight loss and maintenance was needed? – But what about dietary composition (<30% fat)?
• Educational sessions in Control group? • Statin drop-in in the Control group? • Patients in both groups were reasonably well
managed for CVD risk?
Greater Weight Loss Further Reduces the Incidence of New-Onset Diabetes
Hamman RF, et al. Diabetes Care 29:2102, 2007
-15 -10 5 0 5
20
15
10
5
0
Inci
denc
e ra
te p
er
100
pers
on-y
ears
Change in weight from baseline (kg)
Diabetes Prevention Program =Overall risk at the mean weight loss*
Lifestyle intervention “trumps” genetic risk
Florez J et al, DPP Research Group, NEJM 355:241, 2006
Genetic Risk vs. Lifestyle in T2DM? (TCF7L2 SNP)
The New Options • FDA approved drugs within the last
4 years – Phentermine/Topiramate ER – Lorcaserin – Naltrexone/bupropion – Liraglutide
Neuron Populations in the ARC
Suppress food intake • POMC (proopiomelanocortin) • CART (cocaine- and
amphetamine-regulated transcript)
Two neuron populations with opposing effects on food intake In the hypothalamic arcuate nucleus
(ARC):
Stimulate food intake • NPY (neuropeptide Y) • AgRP (agouti-related peptide)
Phentermine/Topiramate ER Mechanism of Action
• Phentermine – Sympathomimetic amine - NE release
Phentermine Increases Norepinephrine Release
????
Phentermine/Topiramate ER: Mechanism of Action
• Phentermine – Sympathomimetic amine - NE release
• Topiramate – ↑ GABA activity – ↓ AMPA/kainate glutamate receptor – ↓ carbonic anhydrase
Topiramate Action on GABAergic Neurons
Topiramate →
Phentermine/Topiramate ER Prevents Progression to T2DM: SEQUEL
Garvey WT, et al. AJCN 95:297, 2012
P < 0.01
76% P=0.15
54%
Annualized Incidence of T2DM
Effects of Phentermine/Topiramate ER in Patients with T2DM: SEQUEL
Garvey WT, et al. AJCN 95:297, 2012
* ‡ P=0.013 for between-group differences.
LS M
ean ∆
A1C
(%)
6.9 7.3 6.9
Placebo (n=55)
Phen/TPM ER 7.5/46 mg (n=26)
Phen/TPM ER 15/92 mg (n=64)
Placebo (n=227)
Phen/TPM ER 7.5/46 mg (n=153)
Phen/TPM ER15/92 mg (n=295)
Change in A1C Change in Diabetes Medications
Patie
nts
With
Net
Cha
nge*
in
Di a
bete
s M
edic
atio
ns (%
)
‡
‡
A1C (%)
Lorcaserein: Mechanism of Action
• Selective 5-HT2C receptor agonist – ↑ POMC
• ↑ α-MSH – ↓ food intake
Lorcaserin Dose in Obese Patients with Type 2 Diabetes Mellitus: BLOOM-DM
P <0.001, lorcaserin vs. placebo
% o
f pat
ient
s
Lorcaserin 10 mg BID
Lorcaserin 10 mg QD
Placebo 80
60
40
20
10
0
≥5% wt loss ≥10% wt loss
*
*
* *
0
O’Neil PM, et al. Obesity 20:1426, 2012
Proportion of patients who lost ≥5% or ≥10% of body weight from baseline to week 52: Completers
Lorcaserin, Change in Glycemic Parameters: BLOOM-DM
* * * *
* * * *
0.0
-0.5
-1.0
-1.5
0 12 24 36 52
Cha
nge
from
bas
elin
e (%
)
A1C
Study week
* ** *
* * *
0
-10
-20
-30
-40 0 12 24 52
Cha
nge
from
bas
elin
e m
g/dL
)
Fasting plasma glucose
Study week
Lorcaserin 10 mg BID Lorcaserin 10 mg QD Placebo
*P <0.001; **P <0.05 50% Lorcaserin and 26% on placebo achieved A1C < 7.0%
O’Neil PM, et al. Obesity 20:1426, 2012
Newest FDA-Approved Weight Loss Drugs
Agents Action Approval
Bupropion/ Naltrexone
• Dopamine/NE reuptake inhibitor • Opioid receptor
antagonist
• June, 2014
Liraglutide • GLP-1 receptor agonist
• Dec, 2014
Weight Loss in Patients with T2DM with Naltrexone-Bupropion
Hollander P et al, . Diabetes Care 36:422, 2013
Effect of Naltrexone-Bupropion on Hb A1c in Patients with T2DM
Hollander P et al, . Diabetes Care 36:422, 2013
GLP-1 Effects in Humans: Understanding the Metabolic Role of Incretins
Beta cells: Enhances glucose-dependent insulin
secretion
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
GLP-1 secreted upon the ingestion of food
Liver: ↓ Glucagon reduces
hepatic glucose output
Stomach: Helps regulate
gastric emptying
Promotes satiety and reduces appetite
Alpha cells: ↓ Postprandial
glucagon secretion
Liraglutide Approved for Diabetes Also Reduces Body Weight
-5 0 5 10 15 20-10
-8
-6
-4
-2
0Placebo1.2 mg/d1.8 mg/d2.4 mg/d3.0 mg/dOrlistat
Rand
omiz
atio
n
Scre
enin
g
Weeks from Randomization
Wei
ght L
oss
(kg)
Astrup A, et al. Lancet. 374:1606, 2009
Matching Medication to Patient When NOT TO USE: Lorcaserin
– Patient on a lot of SSRI and/or SNRI Orlistat
– GI disorders Phentermine/topiramate
– Pregnant-age women not on birth control
– Uncontrolled HTN – Uncontrolled or active CVD
Naltrexone/bupropion – Suicidal ideation – Uncontrolled HTN
Liraglutide – MCT at risk patients
Thomas EA et al, Obesity 24:37, 2016
Empagliflozin (EMPA-REG)
Adapted from Inzucchi SE et al. Diab Vasc Dis Res 12:90, 2015
BP Arterial stiffness
Glucose Insulin
Albuminuria
Uric acid
Other
↑LDL-C ↑HDL-C TG
Oxidative
stress
Sympathetic nervous system activity
Weight Visceral adiposity
Mingrone G et al, Lancet 386:964, 2015
Bariatric-metabolic Surgery vs. Medical Treatment in Obese Patients with T2DM:
5 Year Follow-up • Primary Objective – to assess 5 year outcomes from a
randomized trial designed to compare surgery with conventional medical treatment for the treatment of T2DM in obese patients. – n = 60 obese patients with T2DM
• Age 30-60 years; BMI ≥ 35.0 kg/m2; A1c ≥ 7.0% • ≥ 5 years duration of T2DM • 20 each assigned to
– Medical treatment – Roux-en-Y gastric bypass 88% 5 year follow-up – Biliopancreatic diversion
– Primary endpoint: A1c of ≤ 6.5% and FPG ≤ 5.6 mmol/L Mingrone G et al, Lancet 386:964, 2015
Bariatric-metabolic Surgery vs. Medical Treatment in Obese Patients with T2DM:
Weight
Mingrone G et al, Lancet 386:964, 2015
Bariatric-metabolic Surgery vs. Medical Treatment in Obese Patients with T2DM:
Remission Rate
Mingrone G et al, Lancet 386:964, 2015
Bariatric-metabolic Surgery vs. Medical Treatment in Obese Patients with T2DM:
Metabolic Improvement
Mingrone G et al, Lancet 386:964, 2015
Bariatric-metabolic Surgery vs. Medical Treatment in Obese Patients with T2DM:CVD
Risk
Mingrone G et al, Lancet 386:964, 2015
Bariatric-metabolic Surgery vs. Medical Treatment in Obese Patients with T2DM:
Cardiovascular Drugs
Mingrone G et al, Lancet 386:964, 2015
Bariatric-metabolic Surgery vs. Medical Treatment in Obese Patients with T2DM: HDL
Cholesterol
Mingrone G et al, Lancet 386:964, 2015
Change in HbA1c: Meta-Analysis of Surgical vs. Medical Trials
Summary and Conclusions • In obese patients weight loss is difficult to
achieve and more difficult to maintain. – There is a strong metabolic basis for this. – However, success can be achieved.
• In patients with T2DM – Lifestyle has many benefits but not CVD event
reduction – Weight loss medications are effective but must be
maintained and CVD benefits remain unproven – Bariatric-metabolic surgery appears most effective in
reducing A1c, but CVD?
Thank You!